Lu-Labeled h-R3 (nimotuzumab), a humanized monoclonal antibody targeting the external domain of the epidermal growth factor receptor

The epidermal growth factor receptor (EGFR) is a 170-kDa transmembrane protein that promotes cell proliferation through a receptor-associated tyrosine kinase (TK)–mediated signal transduction pathway and is known to participate in the development, survival, and migration of normal cells and a variety of cancerous cells (1). In addition, overexpression of the EGFR in malignant tumors appears to correlate with a poor prognostic outcome for the patient (1). In an effort to develop therapies against cancer, a variety of anti-EGFR monoclonal antibodies (mAbs) that inhibit activation of the receptor (see Di Fede et al. (2) for details) or small molecules that interfere with stimulation of the receptor TK pathway (for details, see Kumar et al. (3)) have been developed and approved by the United States Food and Drug Administration for use in the clinic. Vallis et al. developed ior egf/r3, a murine mAb with a high affinity for the extracellular domain of the EGFR, labeled it with 99m-technetium, and used it for the molecular imaging of the receptor (4). However, because of immunogenicity, the Tc-labeled mAb was considered to have limited clinical application, particularly for patients who required repeated imaging investigations. To alleviate this problem, a humanized ior egf/r3 was developed by combining the complementary determining regions of the murine antibody with a human immunoglobulin-1 framework, and this new agent was designated as h-R3 or nimotuzumab (5). Subsequently, Tc-labeled h-R3 was investigated for its tissue distribution and imaging properties in clinical trials using single-photon emission computed tomography (SPECT) (4, 5). From these studies, the investigators concluded that Tc-h-R3 can be used for the detection of tumors that overexpress EGFR, but it showed a high accumulation in the liver and kidneys of the patients. In another clinical study, the biodistribution of Re-labeled h-R3 was investigated with SPECT in patients with high-grade gliomas after locoregional administration; it was shown that this mode of administration of Re-h-R3 was safe and that the radiolabeled mAb could be used for the treatment of this malignancy (6). In a continued effort to develop a radioimmunotherapeutic agent that can be used in the clinic for the radioimmunotherapy of cancerous tumors that overexpress the EGFR, Beckford Vera et al. produced Lu-labeled h-R3 and investigated its biodistribution in healthy mice and mice bearing A431 human cell epithelial carcinoma xenograft tumors (7).